Mutant enzymes impair communication between neurons and cause movement disorders in the SCA34 model

In one type of rare hereditary disorder that affects the control of body movements, scientists have discovered mutations in enzymes that impair communication between neurons. Walk across the street.

Disorders are spinocerebellar ataxia, or SCA, a neurodegenerative condition resulting from various genetic mutations whose debilitating income can include ataxia-; loss of control of body movements-; regulate movement and balance The atrophy of the cerebellum, which is a small part of the brain that is clogged with neurons, says Dr. Ferenc Deark, a neuroscientist at Augusta University’s Medical College of Georgia.

The enzyme is ELOVL4, which produces very long chain fatty acids, and its mutation is known to cause certain SCA types 34. By the age of two months, this SCA-type animal model had motor control problems, and MCG and members of the University’s Center for Scientist Oklahoma Health Sciences wanted to know exactly why.

We found that the synaptic response was dramatically reduced. The information went faster, it went faster, and they didn’t actually receive the message. “

Dr. Ferenc Deák, a neuroscientist at the Medical College of Georgia, Augusta University.

“They were sending signals, but that didn’t happen in mutant knock-in rats when they needed to adjust synaptic connections to coordinate different movements,” he used the gene editing technology CRISPRcas9. Describes the SCA34 model generated in.

Despite the various gene mutations that cause SCA, the common return is to Purkinje cells, the large brain cells of the cerebellum that can receive changes in cerebellar output and about 100 times more input than normal neurons. It seems to be the influence of. Large cells also exclusively block communication, thus shutting down signals that cause interference, such as muscle activation. Loss of these important cells is evident in many forms of SCA, says Deak.

Like a busy airport air traffic controller, these large brain cells are clearly the only neurons that simultaneously monitor many different inputs and send messages from that part of the brain.

Purkinje cells, which are one of the smallest neurons in the brain, receive many inputs from the most abundant granule cells. Both cell types express a lot of ELOVL4 and are also enzyme-dependent, says Deak. ELOVL4 was known to be important for communication between these cells and other cells, but why remained elusive.

A new study found that mutations in ELOVL4 significantly reduced the ability of synapses to exchange messages with Purkinje cells and enhanced signal transduction. This is essential in this case to coordinate the movement. Move your hands violently if necessary or with commands.

Their findings demonstrate the essential role of ELOVL4 in motor function and synaptic plasticity, says Deak.

They also suggest that patients with SCA34 have impaired and asynchronous communication between major neurons in the cerebellum long before the brain shows obvious signs of degeneration.

Over time, these constantly communicating cell-to-cell dysfunctions can lead to cerebellar degeneration that is common in patients when they first see a doctor for gait, conversation, and other movement problems, Deak said. It states that it may be connected.

However, scientists report that in the SCA34 model, the structure of the cerebellum appeared normal up to 6 months of age, even though the animal model clearly had the expected movement disorders.

They found that the synapses were also intact and functioning at a basic level that allowed the rats to walk normally, but these knock-in rats lacked the usual plasticity and flexibility. rice field. Rather, mutant synapses increased signaling and failed to translocate.

ELOVL4 can produce both saturated and unsaturated very long chain fatty acids-; it is called “long” because it contains a large number of carbon atoms-; depending on which tissue the enzyme is in. In the cerebellum, Purkinje cells and granule cells can make saturated very long chain fatty acids, which are known to be important for synaptic function, says Deak. However, it was unclear exactly how important they were.

Scientists believe that the reduced synaptic responsiveness they find is a matter of quantity. The mutated enzyme produces about 70% of the normal amount of very long chain fatty acids, which appears to be the threshold for gait problems. If the cells did not produce anything, it would result in excessive seizures and death, as Deak saw in other models.

Their current research involves finding ways to deliver more saturated very long chain fatty acids to the brain. Scientists are applying for a patent for one way to do this. This is made more difficult by the fact that it has the consistency of candle wax when it produces saturated very long chain fatty acids. Digest and just poop.

Very long chain fatty acids are vital to life, but their exact role is almost elusive, scientists say.

“What we know from our research is that they are very important components for certain cell membranes,” says Deak, like the membranes and skin cells of some excitatory and inhibitory neurons. Says. In fact, scientists have shown that when ELOVL4 is missing in the skin, fluid penetrates through the skin. This is our greatest natural barrier. Deak said that when creating other ELOVL4 mutant mouse models, it was necessary to overexpress ELOVL4, especially in the skin, to allow survival.

According to Deak’s research, these saturated very long chain fatty acids also prefer to accumulate and strengthen vesicles, which are small movement compartments that can move around in the cell, so they reach their destination before fusing with the cell membrane. can. Neurotransmission requires fusion-; One of the vesicles of brain transport is a chemical messenger called a neurotransmitter, but chaotic fusion is bad.

Scientists recorded the effects of discovering that mice with two mutant copies of ELOVL4 died from seizures. While they were making these discoveries in the laboratory, Saudi Arabia reported on children with the same mutations and problems, he says. In fact, it was Deak’s research interest in seizures that prompted him to seek a better understanding of the role of very long chain fatty acids. He suspects they may also play a role in his other interests: aged brain and Alzheimer’s disease.

A team led by Dr. Martin-Paul Agbaga created a “knock-in” rat model of the human state SCA34. This has been confirmed in one French-Canadian family and three Japanese families. In these individuals, skin problems can surface from birth to adolescence, and motor problems and usually progressive movement problems begin to surface in the thirties.

Agbaga, co-author of the new treatise and one of Deak’s longtime collaborators, is a visual scientist and cell biologist at the University of Oklahoma Health Sciences Center Ophthalmology and Dean McGee Eye Institute.

Robert E, founder of the ELOVL4 research group in Oklahoma and a professor of visual research at the Dean McGee Eye Institute, a world leader in research on retinal lipid pathophysiology. Dr. Anderson is the co-author of this treatise. Deak came to MCG from the University of Oklahoma Health Sciences Center last year.

SCA is widespread in humans between the ages of 8 and 60 and has symptoms including poor coordination of hand-eye movements and speech, usually surfaced after age 18. Currently, there is no suitable treatment other than physical therapy. An option for patients with SCA, says Deak.

This study was supported by the National Institutes of Health, the Presbyterian Health Foundation, and studies to prevent blindness.